Inactivation of
 Pasteurella
 (
 Mannheimia
 )
 haemolytica
 Leukotoxin Causes Partial Attenuation of Virulence in a Calf Challenge Model

Highlander, Sarah K.; Fedorova, Natalie D.; Dusek, David; Panciera, Roger J.; Alvarez, Laura E.; Rinehart, Carol L.

doi:10.1128/iai.68.7.3916-3922.2000

Cited by 76 publications

(68 citation statements)

References 39 publications

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“…69,76 LKT-A is a key virulence factor that contributes to the pathogenesis of inflammation and pulmonary necrosis in SF, and it is specific for ruminant leukocytes. 54,117 In diseased lungs, LKT is associated with the cell membranes of degenerating inflammatory cells located in alveoli. 124 Although most strains of M haemolytica from cattle and sheep produce LKT, not all strains are equally pathogenic, because LKT from these strains do not exhibit similar leukotoxic activity and the amount of LKT produced is variable.…”

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confidence: 99%

“…36,103,104 The importance of LKT in causing pulmonary necrosis was established by intratracheal inoculation of calves with a LKT-deficient mutant M haemolytica, which caused lower mortality and decreased lung lesions, as compared to animals challenged with the parent strain capable of producing LKT-A. 54,117 M haemolytica-induced pneumonia and other diseases are observed in only ruminants-including cattle, sheep, bighorn sheep, goats, bison, and exotic ruminants-because LKTinduced effects are specific for ruminant macrophages, lymphocytes, neutrophils, and platelets. 34,35 This species specificity stems from the selective interaction of LKT with the b 2 integrin LFA-1 (lymphocyte function-associated antigen 1; CD11a/CD18) on target host cells.…”

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confidence: 99%

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Mannheimia haemolytica

2010

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Mannheimia haemolytica serotype S1 is considered the predominant cause of bovine pneumonic pasteurellosis, or shipping fever. Various virulence factors allow M haemolytica to colonize the lungs and establish infection. These virulence factors include leukotoxin (LKT), lipopolysaccharide, adhesins, capsule, outer membrane proteins, and various proteases. The effects of LKT are species specific for ruminants, which stem from its unique interaction with the bovine b2 integrin receptor present on leukocytes. At low concentration, LKT can activate bovine leukocytes to undergo respiratory burst and degranulation and stimulate cytokine release from macrophages and histamine release from mast cells. At higher concentration, LKT induces formation of transmembrane pores and subsequent oncotic cell necrosis. The interaction of LKT with leukocytes is followed by activation of these leukocytes to undergo oxidative burst and release proinflammatory cytokines such as interleukins 1, 6, and 8 and tumor necrosis factor a. Tumor necrosis factor a and other proinflammatory cytokines contribute to the accumulation of leukocytes in the lung. Formation of transmembrane pores and subsequent cytolysis of activated leukocytes possibly cause leakage of products of respiratory burst and other inflammatory mediators into the surrounding pulmonary parenchyma and so give rise to fibrinous and necrotizing lobar pneumonia. The effects of LKT are enhanced by lipopolysaccharide, which is associated with the release of proinflammatory cytokines from the leukocytes, activation of complement and coagulation cascade, and cell cytolysis. Similarly, adhesins, capsule, outer membrane proteins, and proteases assist in pulmonary colonization, evasion of immune response, and establishment of the infection. This review focuses on the roles of these virulence factors in the pathogenesis of shipping fever.

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Mannheimia haemolytica

2010

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“…Two viral regulatory proteins, bICP0 and bICP27, inhibit interferon-dependent transcription (3,(15)(16)(17)(18). Infection also erodes mucosal surfaces within the upper respiratory tract, which promotes establishment of bacterial pathogens in the lower respiratory tract (19)(20)(21).…”

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Bovine Herpesvirus 1 Regulatory Proteins bICP0 and VP16 Are Readily Detected in Trigeminal Ganglionic Neurons Expressing the Glucocorticoid Receptor during the Early Stages of Reactivation from Latency

Silva

Kook

Doster

et al. 2013

J Virol

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Bovine herpesvirus 1 (BHV-1) establishes a lifelong latent infection in sensory neurons following acute infection. Increased corticosteroid levels, due to stress, increases the incidence of reactivation from latency. Within minutes, corticosteroids activate the glucocorticoid receptor and transcription of promoters containing a glucocorticoid receptor element. A single intravenous injection of the synthetic corticosteroid dexamethasone consistently induces reactivation from latency in calves. Lytic cycle viral gene expression is detected within 6 h after dexamethasone treatment of calves latently infected with BHV-1. Cellular transcription factors are induced by dexamethasone in trigeminal ganglionic neurons within 1.5 h after dexamethasone treatment, suggesting they promote viral gene expression during the early phases of reactivation from latency, which we operationally defined as the escape from latency. In this study, immunohistochemistry was utilized to examine viral protein expression during the escape from latency. Within 1.5 h after dexamethasone treatment, bICP0 and a late protein (VP16) were consistently detected in a subset of trigeminal ganglionic neurons. Most neurons expressing bICP0 also expressed VP16. Additional studies revealed that neurons expressing the glucocorticoid receptor also expressed bICP0 or VP16 at 1.5 h after dexamethasone treatment. Two other late proteins, glycoprotein C and D, were not detected until 6 h after dexamethasone treatment and were detected in only a few neurons. These studies provide evidence that VP16 and the promiscuous viral trans-activator (bICP0) are expressed during the escape from latency, suggesting they promote the production of infectious virus in a small subset of latently infected neurons. Bovine herpesvirus 1 (BHV-1) induces clinical disease in the upper respiratory tract, nasal cavity, or ocular cavity of cattle. BHV-1 establishes latency in sensory neurons but periodically reactivates from latency and consequently is widespread in cattle (1-4). Infection inhibits cell-mediated immunity (5-8) and CD8 ϩ T cell recognition of infected cells (9-12) and induces apoptosis in CD4 ϩ T cells (13,14). Two viral regulatory proteins, bICP0 and bICP27, inhibit interferon-dependent transcription (3,(15)(16)(17)(18). Infection also erodes mucosal surfaces within the upper respiratory tract, which promotes establishment of bacterial pathogens in the lower respiratory tract (19-21).The incidence of BHV-1 reactivation from latency is increased following stressful stimuli that increase corticosteroid levels (reviewed in references 22, 23, and 24). Regardless of the reactivation stressor, lytic cycle viral gene expression, which is nearly undetectable during latency, must be activated. Administration of the synthetic corticosteroid dexamethasone (DEX) to latently infected calves or rabbits initiates BHV-1 reactivation from latency 100% of the time (1,2,4,(25)(26)(27). Six hours after DEX treatment, lytic cycle viral RNA expression is readily detected in a subset of trigem...

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“…It has been reported that LktC-mediated acylation is essential for the biological effects of the toxin, including the induction of apoptosis (20,21). However, an LktC mutant strain that we (S. K. Highlander) developed previously was only partially attenuated in its virulence in a calf challenge model (22). We reasoned that further elucidation of the role of LktC-induced acylation in the cytotoxic activity of Lkt would be facilitated by characterizing the effects of LktC mutant toxin using target cells that are more susceptible to Lkt than are bovine or ovine cells, which are usually studied in the context of Lkt virulence and activity.…”

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Acylation Enhances, but Is Not Required for, the Cytotoxic Activity of Mannheimia haemolytica Leukotoxin in Bighorn Sheep

et al. 2015

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c Mannheimia haemolytica causes pneumonia in domestic and wild ruminants. Leukotoxin (Lkt) is the most important virulence factor of the bacterium. It is encoded within the four-gene lktCABD operon: lktA encodes the structural protoxin, and lktC encodes a trans-acylase that adds fatty acid chains to internal lysine residues in the protoxin, which is then secreted from the cell by a type 1 secretion system apparatus encoded by lktB and lktD. It has been reported that LktC-mediated acylation is necessary for the biological effects of the toxin. However, an LktC mutant that we developed previously was only partially attenuated in its virulence for cattle. The objective of this study was to elucidate the role of LktC-mediated acylation in Lkt-induced cytotoxicity. We performed this study in bighorn sheep (Ovis canadensis) (BHS), since they are highly susceptible to M. haemolytica infection. The LktC mutant caused fatal pneumonia in 40% of inoculated BHS. On necropsy, a large number of necrotic polymorphonuclear leukocytes (PMNs) were observed in the lungs. Lkt from the mutant was cytotoxic to BHS PMNs in an in vitro cytotoxicity assay. Flow cytometric analysis of mutant Lkt-treated PMNs revealed the induction of necrosis. Scanning electron microscopic analysis revealed the presence of pores and blebs on mutant-Lkt-treated PMNs. Mass spectrometric analysis confirmed that the mutant secreted an unacylated Lkt. Taken together, these results suggest that acylation is not necessary for the cytotoxic activity of M. haemolytica Lkt but that it enhances the potency of the toxin. Mannheimia haemolytica is a respiratory pathogen of domestic and wild ruminants (1-3). It is the most important bacterial pathogen of bovine respiratory disease complex, which costs the U.S. cattle industry alone more than $1 billion (4). M. haemolytica is also an important pathogen of pneumonia in bighorn sheep (Ovis canadensis) (BHS), which is the primary disease responsible for the drastic decline of BHS populations in North America from an estimated 2 million animals in the 1800s to less than 70,000 at the present time (5). Under the experimental conditions, M. haemolytica consistently caused 100% mortality in BHS within 2 to 3 days (6-8). The bacterium possesses several virulence factors, including the capsule, outer membrane proteins, lipopolysaccharide, and leukotoxin (Lkt). Based on the fact that Lkt deletion mutants do not cause mortality (6) or cause reduced mortality and milder lung lesions (9, 10), Lkt has been accepted as the primary virulence factor of M. haemolytica. The 104-kDa Lkt is absolutely specific for ruminant leukocytes (11). Previously, we have shown that the molecular basis for the ruminant specificity of Lkt rests in its binding to the signal peptide of CD18; the signal peptide remains intact in mature CD18 molecules on ruminant leukocytes, unlike that of nonruminants, which is cleaved (12). Although all ruminant leukocyte subsets are susceptible to Lkt-induced cytolysis, polymorphonuclear leukocytes (PMNs) are the most su...

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Inactivation of Pasteurella ( Mannheimia ) haemolytica Leukotoxin Causes Partial Attenuation of Virulence in a Calf Challenge Model

Cited by 76 publications

References 39 publications

Mannheimia haemolytica

Mannheimia haemolytica

Bovine Herpesvirus 1 Regulatory Proteins bICP0 and VP16 Are Readily Detected in Trigeminal Ganglionic Neurons Expressing the Glucocorticoid Receptor during the Early Stages of Reactivation from Latency

Acylation Enhances, but Is Not Required for, the Cytotoxic Activity of Mannheimia haemolytica Leukotoxin in Bighorn Sheep

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